Crystallization method for purification of calcipotriene

Abstract

Provided is a crystallization method for reducing the level of impurities in calcipotriene in which a solution of a starting calcipotriene in a first process solvent, for example THF, is combined with second process solvent, for example methyl formate, and, after cooling, calcipotriene is isolated. The method can include a slurry step for reducing the level of residual first process solvent.

1 - 27 . (canceled) 
     
     
         28 . A method of preparing crystallized calcipotriene having a reduced level of impurities comprising the steps of:
 combining calcipotriene, a first solvent selected from lower alkyl alcohols, lower aliphatic ketones, alkyl esters of lower carboxylic acids, and cyclic ethers, and an antisolvent to form a mixture; and   precipitating calcipotriene from the mixture.   
     
     
         29 . The method of  claim 28 , wherein the antisolvent to first mixture ratio is about 1 to 100 by volume. 
     
     
         30 . The method of  claim 28 , wherein the precipitating step comprises cooling the mixture. 
     
     
         31 . The method of  claim 28 , wherein the combining step comprises dissolving calcipotriene in the first solvent prior to admixing with the antisolvent. 
     
     
         32 . The method of  claim 28 , wherein the first solvent is a cyclic ether and the antisolvent is methyl formate. 
     
     
         33 . The method of  claim 32 , wherein the cyclic ether is tetrahydrofuran. 
     
     
         34 . The method of  claim 28 , wherein the first solvent is a lower alkyl alcohol and the antisolvent is a lower hydrocarbon. 
     
     
         35 . The method of  claim 34 , wherein the first solvent is iso-propyl alcohol and the antisolvent is hexane. 
     
     
         36 . The method of  claim 28 , wherein the first solvent is a lower dialkyl ketone and the antisolvent is methyl formate. 
     
     
         37 . The method of  claim 36 , wherein the first solvent is acetone and the antisolvent is methyl formate. 
     
     
         38 . The method of  claim 28 , wherein the first solvent forms a solution of calcipotriene having a concentration of at least about 20% (w/v), relative to the first solvent. 
     
     
         39 . The method of  claim 28 , wherein the first solvent forms a solution of calcipotriene having a concentration of at least about 25% (w/v), relative to the first solvent. 
     
     
         40 . The method of  claim 30 , wherein the cooling step comprises cooling at a rate of less than about 20° C. per hour. 
     
     
         41 . The method of  claim 30 , wherein the cooling step comprises cooling at a rate of less than about 10° C. per hour. 
     
     
         42 . The method of  claim 30 , wherein the cooling step comprises cooling the mixture to less than about −10° C. 
     
     
         43 . The process of  claim 28 , wherein the calcipotriene has an average particle size of about 15μ to about 40μ. 
     
     
         44 . The process of  claim 28 , wherein the calcipotriene has less than about 0.1% each of C 3 —OH, C 21 , C 24 —OH, and C 5  E isomers. 
     
     
         45 . The process of  claim 28 , wherein the calcipotriene has less than 1% total impurities. 
     
     
         46 . The process of  claim 28 , wherein the calcipotriene has less than 0.5% total impurities. 
     
     
         47 . The process of  claim 28 , wherein the calcipotriene has less than 0.3% total impurities. 
     
     
         48 . The process of  claim 28 , wherein the calcipotriene has less than 0.1% total impurities. 
     
     
         49 . The process of  claim 28 , wherein the calcipotriene is free from water. 
     
     
         50 . The process of  claim 28 , wherein the combination is cooled to a temperature of less than about −10° C. 
     
     
         51 . Calcipotriene prepared by the process of  claim 28 .